Wound treatment has become a more highly developed area of scientific and commercial investigation as new research has revealed the workings of the healing process. More rapid healing of a wound reduces long term healthcare costs and improves patient recovery, including regaining of sensation, function and aesthetics.
Healing, like all other biological processes, is a cellular process. The occurrence of an injury immediately triggers the onset of this process, which continues until the injury is healed. Although its exact mode of action is not yet understood, it is clear that a feedback mechanism monitors the extent of tissue damage and adjusts cellular activity in the injured area to produce the exact amount of healing needed.
As used herein, the terms "wound" and "injury" refer to tissue damage or loss of any kind, including but not limited to, cuts, incisions (including surgical incisions), abrasions, lacerations, fractures, contusions, burns, amputations and the like.
Healing processes can be classified into three types, determined by how the cells in the injured area react to the injury. The simplest type of healing is scarification healing, wherein cells at the edges of a wound produce collagen and elastic fibers which simply bind the edges of the wound together without restoring severed nerves or blood vessels. This type of healing produces a visible scar, and sometimes results in numbness and circulatory inadequacy in the region of the wound and regions distal thereto. In the higher animals, including man, the heart, skeletal muscle, and nerve tissue (including the brain) heal by scarification.
A second type of healing is tissue replacement, wherein the cells of some body tissues produce more cells of their own kind to replace missing portions. In humans, the skin and portions of the gastrointestinal tract heal by replacement. In this type of healing, the replacement rate of the cells in the injured area increases to produce sufficient numbers of cells to help heal the injury, then returns to normal after healing is complete. Replacement is effective only if enough normal cells of the needed types are present in the area, and only for the particular types of cells that are capable of healing in this manner. Replacement is often inadequate for healing full-thickness skin wounds, which frequently heal with limited re-epithelialization, resulting in poorly innervated, thin and inelastic skin, while subcutaneous soft tissue defects heal primarily by scarification. However, such results are generally adequate for function if the wound is on the torso or the extremities (excepting the hand).
The most effective--and most complex--type of healing is regeneration. This type of healing is capable of replacing entire limbs and internal organs, and even portions of the brain and heart, which typically contain multiple types of cellular structures. Regeneration is a biphasic process. In the first phase, normal, mature "differentiated" cells at the site of the injury revert to an embryonic, unspecialized form ("de-differentiated cells"). These de-differentiated cells multiply rapidly, then become activated and demonstrate a variety of energetic processes which may include amitotic division, nuclear transfer, migration of free nuclei into residual tissues, and production of exceptionally large cells containing nuclear material from a number of individual de-differentiated cells (thus, "activated cells" are cells that undergo these processes). It is also believed that de-differentiated cells have a longer lifespan than differentiated cells.
Activation results in the rapid accumulation of a large mass of embryonic cells known as the blastema, which is the essential element for regeneration. The blastema may be viewed as providing the biological raw material needed for rebuilding the missing tissues. Formation of an adequately sized blastema results in complete regeneration of the missing tissues, whereas if the blastema is inadequate in size, only partial or incomplete regeneration takes place (formation of a stunted or incomplete part, or merely regeneration of individual tissue types that are not fully organized into the desired structure).
In the second phase of the regeneration process, the embryonic cells of the blastema respecialize ("re-differentiate") into the various types of cells needed to rebuild the missing tissues and organized structures in complete anatomical detail. The rebuilding process is essentially a recapitulation (albeit on a local scale) of the original embryonic development of the tissues being replaced.
In vertebrates, regenerative healing is found in certain species of amphibians (notably salamanders). It is almost totally lacking in humans, except in the fetus and in very young children (who may regenerate the distal finger tip if the wound is left open). In adults, regeneration is largely limited to parts of the fracture healing process. Clearly, it would be beneficial if humans could regenerate other damaged tissues, both in terms of more cost-effective treatment modalities and improved outcomes for patients.
The stimulus which initiates the complex regenerative process in amphibians has been reported to be a specific type of electrical signal, but the mechanism which provides the blueprint for the tissues to be regenerated is largely unknown. In the case of regeneration of individual tissues, however, a number of inducer substances that carry a specific signal causing either embryonic, de-differentiated, or mature cells to convert into specific tissue types have been identified. These "biological inducers" are analogous to chemical catalysts in that they effect cellular transformation by contact with the cells, but the inducer itself does not take part in the transformation. According to one theory, it is believed that biological inducers act by producing a signal in the nature of a specific electrical field which causes an event to occur on the surface of the target cell, which in turn causes the DNA in the target cell to alter the cell type in a specific fashion. By way of example, a "bone induction material" that causes the transformation of muscle cells into bone has been identified (M. Urist, Proc. Nat. Acad. Sci. USA, Vol. 70, pp. 3511-3515 (1973)).
Healing in general is known to be related to the degree of the injury, the amount of nerve tissue present at the site, and the electrical potential difference between the site and surrounding intact tissue (the "current of injury"). In particular, regeneration in amphibians such as salamanders and fracture healing in mammals are associated with complex changes in the local DC (direct current) electric field. An injury results in changes in the electric field and stimulates the animal's neural system, which in turn produces an electrical signal at the site of the injury, stimulating the complex cellular responses that eventually produce healing. The electric field gradually returns to normal, pre-injury levels as the injury heals. Conversely, failure of the normal healing process, as in fracture nonunions, is associated with the absence of appropriate electrical signals at the site of the injury.
The antimicrobial and antifungal properties of silver and silver compounds are well known. Topical preparations that contain silver or silver compounds-silver nitrate solution, silver sulfadiazine cream, colloidal silver compositions, silver-protein compounds such as Argyrol.TM., and so forth, are widely used in medicine. The useful effects of these compositions are due to the small amounts of free silver ions produced by dissociation of the silver compound or to formation of toxic byproducts in situ.
The effectiveness of silver as an antimicrobial agent is at least partly determined by the delivery system. Most silver compounds that dissociate readily and produce large numbers of free silver ions are highly toxic to mammalian (including human) tissues Less-toxic compounds, including silver sulfadiazine cream (widely used in the treatment of burns) and silver nitrate solution, do not dissociate readily and therefore do not release large numbers of silver ions. These compounds must be re-applied frequently to maintain their clinical efficacy.
Electrically-generated silver ions, which can penetrate more deeply into the tissues, are effective even against antibiotic-resistant strains of bacteria, fungi, etc., inhibiting growth in vivo and in vitro at current densities as low as 10 nA/mm.sup.2 and silver ion concentrations as low as 0.5 mg/ml. The effects of electrically-generated silver ions are described in a number of publications, including the following: J. A. Spadaro et al., "Antibacterial Effects of Silver Electrodes with Weak Direct Current," Antimicrobial Agents & Chemotherapy, Vol. 6, pp. 637-642 (1974); T. J. Berger et al., "Antifungal Properties of Electrically Generated Metallic Ions," Antimicrobial Agents & Chemotherapy, Vol. 10, pp. 856-860 (1976); R. O. Becker et al., "Treatment of Orthopedic Infections With Electrically-Generated Silver Ions," J. Bone & Joint Surgery, Vol. 60-A, pp. 871-881 (1978).
Silver and other metals are widely used in wound dressings and materials therefor. Fabo (U.S. Pat. No. 5,340,363) discloses a dressing that includes an outer absorbent layer and an inner porous, hydrophobic layer knitted of elastic threads and encapsulated by a soft, hydrophobic silicone or polyurethane gel. The gel can be used as a carrier for antibacterial agents such as zinc, pain-relieving substances, and agents that stimulate wound repair. Klippel et al. (U.S. Pat. No. 3,830,908) use micronized allantoin as a carrier for a bactericidal or bacteristatic ingredient (such as silver citro allantoinate) that is dispersed on the surface of a plastic air splint or other bandaging product. This material depends on the separation of the molecular moieties to provide the antibacterial action.
McKnight et al. (U.S. Pat. No. 3,800,792) disclose a surgical dressing having a layer of tanned, reconstituted collagen foam film laminated to a thin, continuous layer of an inert polymer. The collagen layer contains finely-divided silver metal added by soaking the collagen film in Tollen's reagent. Stowasser (U.S. Pat. No. 2,934,066) makes a dressing of absorbent, metal-coated fibers, such as a carding fleece coated with aluminum and backed by compressed cellulose, and polyamide fibers coated with vacuum-deposited silver.
Dressings for provision of electrical stimulation are also known. For example, Jones (U.S. Pat. No. 4,911,688) covers a wound with a clear cover that serves as a hollow chamber for holding a fluid such as saline in contact with a wound. When connected to a voltage source, a metal anode and a return electrode create free ions and an electrical field to enhance healing and tissue regeneration. Juhasz (U.S. Pat. No. 4,817,594) discloses a multi-layer dressing for covering discharging, malodorous wounds. The dressing includes a layer of an electrically-conductive material such as silver and a layer of charcoal fabric. Application of a DC (direct current) voltage to the conductive layer drives silver ions into the wound to enhance tissue growth and inhibit bacterial growth; application of transcutaneous AC (alternating current) is used for post-operative pain relief. Seiderman (U.S. Pat. No. 4,767,401) describes a bandage-like device used for iontophoretic administration of medicaments, including silver-protein colloids. The device includes a metal foil electrode (preferably aluminum), and makes use of the slight inherent negative electric charge proximate a wound site to generate a small electric field at the site.
Matson (U.S. Pat. No. 4,728,323) coats a substrate (nylon fabric, polymeric film, fiberglass, gauze or polyurethane foam) with a film of a silver salt deposited by vapor or sputter coating techniques. Alternatively, fibers can be coated and then woven or knitted into a fabric. Konikoff (U.S. Pat. No. 4,142,521) shows a bandage or surgical sponge material incorporating one or more electret elements, each electret providing a small electrostatic field to the area of the wound.
In U.S. application Ser. No. 08/524,134, filed Sep. 4, 1995, Becker et al. disclose a bimetallic fabric woven of nylon fibers coated with a first metal such as silver, interspaced at intervals with fibers coated with a second metal such as gold or platinum, preferably in a ratio of about 10:1. Alternatively, deposits of the second metal are placed on a fabric that contains the first metal. When contacted with an electrolyte, each contact junction between the first and second metals serves as a bimetallic junction that produces free silver ions. The material may be used in therapeutic or prophylactic treatment of wounds (including surgical incisions). An iontophoretic system for promoting tissue healing processes and inducing regeneration is described in Becker et al., U.S. application Ser. No. 08/623,046, filed Mar. 28, 1996. The system is implemented by placing a flexible, silver-containing anode in contact with the wound, placing a cathode on intact skin near the anode, and applying a wound-specific DC voltage between the anode and the cathode. Electrically-generated silver ions from the anode penetrate into the adjacent tissues and undergo a sequence of reactions leading to formation of a silver-collagen complex. This complex acts as a biological inducer to cause the formation in vivo of an adequate blastema to support regeneration. The above systems have limitations in that either an electrolyte or an external voltage source is required.
Regardless of whether silver is provided in the form of silver ions or as a topical composition (silver nitrate solution, silver sulfadiazine cream, or the like), its beneficial effects are manifested primarily at the treated surface and immediately adjacent tissues, and are limited by the achievable tissue concentration of silver ions. Despite the availability of numerous techniques for the delivery of silver and silver compounds in vitro and in vivo, there remains a need for a delivery system that is capable of supplying clinically useful concentrations of silver ions to a treatment site without the need for adjuvant electrical stimulation.